Cell Death & Differentiation

2025

The mechanisms that mediate endocrine therapy resistance remain incompletely understood. We identified promyelocytic leukemia protein isoform 1 (PML1) as a central node of this resistance. We established a PML1 gene signature that strongly correlates with PI3K, MAPK, and endocrine resistance signatures across multiple patient cohorts, predicting poor clinical outcomes. Mechanistically, PML1 promotes a self-reinforcing survival circuit by inducing the expression of CCL5 and HBEGF, which activate PI3K and MAPK signaling in an autocrine/paracrine manner. Reciprocally, ERK activation stabilizes PML1 protein, whereas activated mTOR increases PML1 protein synthesis, thereby establishing a positive feedback loop that sustains cancer cell survival under therapeutic pressure. Paradoxically, selective ER degraders (SERDs) and modulators (SERMs) induce PML1 protein accumulation. Fulvestrant, a SERD, while inducing ER protein degradation, rapidly activates PI3K and MAPK pathways, driving PML1 protein accumulation. Consistently, we observed an inverse relationship between ER and PML protein levels. In therapy-sensitive wild-type ER cells with low basal PML1 levels and PI3K/MAPK activity, fulvestrant’s ER-suppressive effects overcome drug-induced elevated PML1 and PI3K/MAPK activity, thereby maintaining therapeutic efficacy. In contrast, in therapy-resistant ER Y537S mutant cells or cells with PML gene amplification, fulvestrant-mediated amplification of constitutively hyperactive PML1-PI3K/MAPK feedback loops dominates over cytotoxic effects, resulting in enhanced cell survival. Notably, reducing PML1 levels through knockdown or arsenic trioxide (ATO), an FDA-approved PML1 degrader, disrupts this resistance circuit and restores endocrine sensitivity. Treatment of ATO resensitizes ER Y537S-bearing resistant tumors to endocrine therapy in xenograft models. These findings establish PML1 as a central hub of resistance, linking ER signaling to the activation of the PI3K/MAPK survival pathway.

Fibroadipogenic progenitors (FAPs) play a key role in skeletal muscle homeostasis and regeneration. They produce extracellular matrix components and secrete cytokines that regulate muscle stem cell function. The number of FAPs and their activity need to be dynamically regulated to avoid their chronic accumulation and overproduction of fibrosis. However, the intrinsic factors by which FAPs control their cell fate decisions remain elusive. Here, we show that FAPs-secreted prostaglandin-E2 (PGE2) functions as a key autoregulatory factor. Using lipidomics and single cell transcriptomics, we show that FAPs are a main cellular source of PGE2 in resting muscle and during regeneration. FAP-secreted PGE2 exerts paracrine effects that maintain the muscle stem cell pool at steady state and stimulate their proliferation post-injury. Moreover, it functions as an autocrine regulator of FAP fate decisions (apoptosis) and subpopulation dynamics. Acute or chronic administration of non-steroidal anti-inflammatory drugs that inhibit the prostaglandin-synthesizing enzyme COX2 increases FAPs content post-injury. Using Pdgfrα-CreERT2_Cox2flox mice, we showed that conditional ablation of COX2 specifically in FAPs increases FAPs content, fibrosis, and impairs muscle regeneration, which can be rescued by PGE2 administration. Furthermore, we show that PGE2 production in FAPs is impaired in mouse models of Duchenne muscular dystrophy, and we provide a proof-of-concept that PGE2 administration can reduce FAPs numbers, fibrosis accumulation, and increase muscle strength. Overall, we uncover a novel role for PGE2 beyond its function in inflammation and identify a mechanism by which FAPs intrinsically regulate their own cell fate, revealing therapeutic potential for muscle injury and dystrophic conditions.

doi: 10.1038/s41418-026-01781-ypmid: 42271069

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options and high recurrence rates. Given the high immunogenicity of TNBC, immune checkpoint inhibitors have been recently incorporated into its treatment. However, immunotherapy extends survival in only a subset of patients, denoting an urgent need to better understand the regulatory mechanisms that shape TNBC-immune microenvironment interactions. In this study, we identified the promyelocytic leukemia PML protein as a new modulator of TNBC immunogenicity. By measuring transcriptional responses to PML perturbation in TNBC cells we found that PML supports chronic activation of inflammatory pathways, resulting in constitutive upregulation of immunosuppressive genes, including PD-L1. Accordingly, PML silencing in a TNBC mouse model led to a substantial reorganization of the tumor microenvironment, with accumulation of various T cell populations linked to immune activation and tumor rejection. Importantly, analysis of human TNBC datasets linked high PML levels to chronic expression of inflammatory gene sets and impaired immune activation in the tumor microenvironment. In parallel, mechanistic studies, including PML interactome mapping and genome-wide DNA methylation profiling, showed that PML cooperates with DNMT1 to repress HLA gene expression via CpG methylation, thereby impairing tumor recognition and T cell-mediated killing. In sum, this study identifies PML as a key mediator of immune evasion in TNBC by concomitantly fostering an immunosuppressive tumor microenvironment and suppressing antigen presentation and tumor recognition by T cells. As PML-targeting therapies are clinically available for leukemia patients, our findings position PML as a promising actionable target to enhance immune responses and improve outcomes for patients with TNBC.

doi: 10.1038/s41418-026-01761-2pmid: 42265413

Patients with cancer who are treated for tumors located in the abdominopelvic region may develop radiation proctitis. This condition is characterized by severe mucosal inflammation that can significantly impair quality of life. In the colon, it’s now established that the stroma orchestrates epithelial, endothelial, and immune cell homeostasis and plays a pivotal role following an injury. A more comprehensive understanding of the underlying mechanisms responsible for digestive mucosa injury and regeneration processes would enable therapeutic targets to be identified for limiting or even treating digestive lesions caused by radiotherapy. In this work, single-cell RNA sequencing was combined with spatial transcriptomics (ST) for an in-depth characterization of colonic stromal cells, highlighting their heterogeneity, their specific functions and interactions in homeostasis, and changes they undergo following localized colon irradiation. The present study identifies the Edil3 marker, (EGF-like repeats and discoidin domains 3), that distinguishes the most abundant stromal population, alongside the previously characterized trophocytes and telocytes. We propose the term “mesitocytes”, from the ancient Greek “mesítês” (“intermediary”), for this stromal subtype, in accordance with both their position along the crypt axis and their role in the BMP/Wnt gradient. After irradiation, we demonstrate the deregulation of the stromal compartment, with an increase of genes involved in immune response, angiogenesis, and regenerative epithelial process. Specifically in the ulcerated area, Edil3 mesitocytes and telocytes are no longer detected by ST. Instead, inflammation-associated fibroblasts (IAFs) emerge, characterized by a distinct transcriptomic signature, including Ereg, Igfbp5, Il11 and C3. This feature is substantiated by analysis of human transcriptomic data which underscores the significance of our findings. Cell fate analysis further clarifies the origins of IAFs, identifying Edil3 mesitocytes as their main source. Furthermore, we observe that IAFs cooperate with endothelial cells, and we also demonstrate IAF-specific molecules involvement in epithelial disruption and endothelial activation, suggesting their key role in disease progression.[graphic not available: see fulltext]

Despite advances in the treatment of metastatic colorectal cancer (mCRC), it remains the second leading cause of cancer-related mortality, with limited effective therapeutic options. While EGFR inhibition is a standard first-line therapy for mCRC patients lacking KRAS mutations, resistance frequently develops, limiting its clinical benefit. Murine CRC models have shown that EGFR deletion in myeloid cells reduces tumor burden, and the presence of EGFR-positive myeloid cells is associated with poor prognosis in mCRC patients. However, the role of these cells in the therapeutic response to anti-EGFR therapies remains poorly understood. In this study, we integrated mouse models, single-cell RNA sequencing (scRNAseq), proteomics, and patient-derived mCRC datasets to investigate how EGFR signaling in myeloid cells shapes the tumor microenvironment (TME). In a preclinical therapeutic trial, we demonstrate that EGFR deletion in myeloid cells of tumor-bearing CRC mice reduced tumor growth, whereas EGFR loss in intestinal epithelial tumor cells alone had no therapeutic impact. EGFR deletion also decreased the abundance of F4/80hi macrophages, particularly the Spp1+ and C1qc+ subsets, and reduced inflammatory pathways like TGFβ, IFNγ, and JAK/STAT signaling in myeloid cells. These changes altered myeloid–T cell interactions, resulting in a less immunosuppressive TME characterized by reduced immune checkpoint expression. Furthermore, we identified thrombospondin-1 (THBS1) as a myeloid-derived ligand interacting with T cells, and confirmed its regulation by EGFR signaling through proteomic analysis. Analysis of human CRC datasets revealed that high EGFR and THBS1 expression correlates with poor patient outcomes. Collectively, these findings establish EGFR signaling in myeloid cells as a critical regulator of the immunosuppressive TME and suggest that targeting EGFR within specific myeloid subsets could represent a promising therapeutic strategy in mCRC.[graphic not available: see fulltext]

doi: 10.1038/s41418-026-01775-wpmid: 42236908

Acyl-CoA–binding protein (ACBP, encoded by diazepam binding inhibitor, DBI) is an abundant intracellular regulator of lipid metabolism that also circulates systemically, yet the mechanisms governing its release and its relationship to organ injury remain unresolved. Herein, we combine human multi-omics, mechanistic mouse models and controlled cell death assays to identify cell death–driven liberation of intracellular ACBP/DBI as a unifying mechanism underlying its elevation in disease. In a cohort of 1198 hospitalized adults, among whom 75% were acutely infected by SARS-CoV-2, plasma ACBP/DBI tightly correlated with inflammatory markers and biochemical signatures of cardiac, hepatic, renal, metabolic and hematologic dysfunction. SomaScan proteomics further revealed that ACBP/DBI co-varies with organ-enriched proteins, particularly those originating from skeletal muscle and pancreas, implicating tissue injury as a major determinant of its circulating abundance. Multiple forms of acute organ damage in mice, including hepatic or renal ischemia-reperfusion, bile duct ligation, pancreatitis and rhabdomyolysis, triggered rapid and robust increases in plasma ACBP/DBI. Using defined in vitro paradigms, we demonstrate that apoptosis, ferroptosis and necroptosis each cause loss of intracellular ACBP/DBI and its release upon plasma membrane permeabilization, independent of the upstream lethal pathway. These mechanistic insights translated in vivo: hepatocyte apoptosis, ferroptosis and necroptosis each elevated circulating ACBP/DBI in a manner attenuated by pathway-specific inhibitors. Finally, meta-analysis of >100,000 individuals across diverse populations revealed that elevated plasma ACBP/DBI consistently associates with systemic and organ-specific disease and predicts future morbidity. Together, our findings identify cell death–driven ACBP/DBI release as a conserved mechanism linking organ injury to increased plasma ACBP/DBI, positioning this molecule as an integrative biomarker of tissue damage across species, organs, and cell death modalities.